Hepatitis C Viral RNA Genotype 3 NS5A Drug Resistance

Question 1. What are hepatitis C virus (HCV) NS5A inhibitors?

NS5A inhibitors are antiviral drugs. They are classified as direct acting agents (DAAs) and work by inhibiting the HCV NS5A protein.1,2

Question 2. Which NS5A inhibitors are approved for clinical use to treat HCV genotype 3?

Daklinza® (daclatasvir) was approved by the FDA in July 2014 for use in genotype 3 in combination with the NS5B inhibitor sofosbuvir.3 Velpatasvir, a pangenotypic NS5A inhibitor included in the medication EPCLUSA®(sofosbuvir + velpatasvir), was approved by the FDA in June 2016.4 Additional NS5A inhibitors are currently under FDA review or are undergoing clinical trials.

Question 3. Which method is used to test for HCV NS5A inhibitor resistance?

Question 4. What is the clinical significance of genotype 3 NS5A resistance-associated variants (RAVs) for patients treated with a daclatasvir-containing regimen?

NS5A RAVs are associated with a lower sustained virologic response (SVR) in patients with HCV genotype 3 who are being treated with daclatasvir and sofosbuvir for 12 weeks. In a phase 3 clinical trial, patients with a baseline Y93H polymorphism had an SVR of 54%, while those without Y93H had an SVR of 92%.3,7 Among patients with HCV genotype 3 and cirrhosis, 1 in 4 (25%) of those with Y93H achieved an SVR at week 12 compared to 19/28 (68%) of those without Y93H.3,7 In a follow-up study, most patients with cirrhosis and RAVs achieved an SVR when treated for 12 or 16 weeks with sofosbuvir, daclatasvir, and ribavirin.8

Question 5. What is the clinical significance of genotype 3 NS5A resistance-associated variants (RAVs) for patients treated with a velpatasvir-containing regimen?

NS5A RAVs are associated with a lower sustained virologic response (SVR) in patients with HCV genotype 3 who are being treated with velpatasvir and sofosbuvir for 12 weeks. In a phase 3 clinical trial, the SVR rate was 88% for patients with any NS5A RAVs at baseline, 84% for patients with Y93H at baseline, and 97% for patients without baseline RAVs.10 For all 10 genotype 3a patients with virologic failure, Y93H was observed at the time of failure.4

The AASLD and IDSA guidelines currently recommend NS5A drug resistance testing for cirrhotic patients. If the NS5A Y93H mutation is present, ribavirin along with sofosbuvir and either daclatasvir or velpatasvir is recommended.9

Question 7. What is the recommended HCV viral load for NS5A resistance testing?

We recommend specimens being submitted for NS5A resistance testing have an HCV RNA level of at least 1,000 IU/mL. The assay may fail at lower viral loads.

This FAQ is provided for informational purposes only and is not intended as medical advice. A clinician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.